叉头框 M1 (FOXM1) 是有丝分裂的关键调节因子，被确定为与多种人类恶性肿瘤有关的癌基因。然而，它如何诱发癌变以及相关的治疗方法仍不完全清楚。在本研究中，我们旨在鉴定涉及FOXM1及其靶基因DEP结构域包含1（DEPDC1）的调控轴并研究它们的生物学功能。 FOXM1 与启动子结合并转录诱导 DEPDC1 表达，反过来，DEPDC1 与 FOXM1 发生物理相互作用，促进其核转位，并增强其转录活性。 FOXM1/DEPDC1 轴对于癌细胞是不可或缺的，事实证明，DEPDC1 可以挽救 FOXM1 敲低引起的细胞生长抑制，并且沉默 DEPDC1 可以有效减弱小鼠肝细胞癌模型中的肿瘤生长。此外，在人肝细胞癌样本中观察到 FOXM1/DEPDC1 轴与不良临床结果之间呈强正相关，进一步表明它们在肝癌发生中的重要性。最后，我们尝试利用免疫疗法来靶向 FOXM1/DEPDC1 轴。通过生物信息学分析鉴定了几个针对 FOXM1 或 DEPDC1 的 HLA-A24:02 限制性 T 细胞表位。然后，成功建立了针对 FOXM1262-270 或 DEPDC1294-302 的 T 细胞受体 (TCR) 工程 T 细胞，并证明可以有效根除肿瘤细胞。我们的研究结果强调了 FOXM1/DEPDC1 轴在肿瘤发生过程中的重要性，并表明它们作为免疫治疗靶点的潜力。© 2024 作者。约翰·威利出版的《癌症科学》

Forkhead box M1 (FOXM1) is a key regulator of mitosis and is identified as an oncogene involved in several kinds of human malignancies. However, how it induces carcinogenesis and related therapeutic approaches remains not fully understood. In this study, we aimed to identify a regulatory axis involving FOXM1 and its target gene DEP domain containing 1 (DEPDC1) and investigate their biological functions. FOXM1 bound to the promoter and transcriptionally induced DEPDC1 expression, in turn, DEPDC1 physically interacted with FOXM1, promoted its nuclear translocation, and reinforced its transcriptional activities. The FOXM1/DEPDC1 axis was indispensable for cancer cells, as evidenced by the fact that DEPDC1 rescued cell growth inhibition caused by FOXM1 knockdown, and silencing DEPDC1 efficiently attenuated tumor growth in a murine hepatocellular carcinoma model. Furthermore, strong positive associations between FOXM1/DEPDC1 axis and poor clinical outcome were observed in human hepatocellular carcinoma samples, further indicating their significance for hepatocarcinogenesis. Finally, we attempted to exploit immunotherapy approaches to target the FOXM1/DEPDC1 axis. Several HLA-A24:02-restricted T-cell epitopes targeting FOXM1 or DEPDC1 were identified through bioinformatic analysis. Then, T cell receptor (TCR)-engineered T cells targeting FOXM1262-270 or DEPDC1294-302 were successfully established and proved to efficiently eradicate tumor cells. Our findings highlight the significance of the FOXM1/DEPDC1 axis in the process of oncogenesis and indicate their potential as immunotherapy targets.© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.